Impact of Age and Variant Time Period on Clinical Presentation and Outcomes of Hospitalized Coronavirus Disease 2019 Patients

Objective To evaluate the impact of age and COVID-19 variant time period on morbidity and mortality among those hospitalized with COVID-19. Patients and Methods Patients from the American Heart Association’s Get With The Guidelines COVID-19 cardiovascular disease registry (January 20, 2020-February 14, 2022) were divided into groups based on whether they presented during periods of wild type/alpha, delta, or omicron predominance. They were further subdivided by age (young: 18-40 years; older: more than 40 years), and characteristics and outcomes were compared. Results The cohort consisted of 45,421 hospitalized COVID-19 patients (wild type/alpha period: 41,426, delta period: 3349, and omicron period: 646). Among young patients (18-40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.6; 95% CI, 1.3-2.1), major adverse cardiovascular events (MACE) (OR, 1.8; 95% CI, 1.3-2.5), and in-hospital mortality (OR, 2.2; 95% CI, 1.5-3.3) when compared with presentation during wild type/alpha. Among older patients (more than 40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.2; 95% CI, 1.1-1.3), MACE (OR, 1.5; 95% CI, 1.4-1.7), and in-hospital mortality (OR, 1.4; 95% CI, 1.3-1.6) when compared with wild type/alpha. Among older patients (more than 40 years), presentation during omicron associated with decreased odds of severe COVID-19 (OR, 0.7; 95% CI, 0.5-0.9) and in-hospital mortality (OR, 0.6; 95% CI, 0.5-0.9) when compared with wild type/alpha. Conclusion Among hospitalized adults with COVID-19, presentation during a time of delta predominance was associated with increased odds of severe COVID-19, MACE, and in-hospital mortality compared with presentation during wild type/alpha. Among older patients (aged more than 40 years), presentation during omicron was associated with decreased odds of severe COVID-19 and in-hospital mortality compared with wild type/alpha.


S
evere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for the Coronavirus Disease-2019 (COVID-19) pandemic, was first discovered in Hubei Province, China, in late 2019. 1 Since then, the virus has spread rapidly around the globe.The initial strains discovered included the wild type and alpha variants (B 1.1.7).The delta variant (B.1.617)was discovered in India in late 2020 and became the dominant strain in the United States around the beginning of July 2021.More recently, the omicron variant was discovered in South Africa in November 2021, and became the dominant variant in the United States at the end of 2021. 2,3revious studies have found considerable differences between these 3 predominant variants.5][6][7] Throughout the pandemic, age has also emerged as a significant predictor of COVID-19 outcomes.For example, a large study evaluating the impact of age across 45 countries reported a log linear increase in the infection fatality ratio in those older than 30 years. 8In another study of 5279 people from New York city, age was the strongest risk factor for hospital admission and among the strongest predictors of critical illness. 9lthough previous studies have compared one variant to another, few have compared all major variants to each other in a national population.Furthermore, few large studies have evaluated the differential impact of age across all 3 variants.Herein, we address this evidence gap and utilize a large national US database to evaluate the impact of age and variant time period on patient characteristics, treatment patterns, and clinical outcomes among patients hospitalized with COVID-19.

METHODS
The American Heart Association's (AHA) Get With The Guidelines (GWTG) COVID-19 cardiovascular disease registry was created to serve as an in-patient data repository for hospitalized adult COVID-19 patients aged 18 years or older with the aim of supporting quality improvement and research.The registry was launched in April 2020 and includes 134 hospitals, health centers, and medical centers from 34 states across the United States.An institutional review board either waived review or approved patient enrollment at the participating centers.Full details of the registry have been previously described. 10sing the AHA's GWTG COVID-19 registry, we identified patients hospitalized across the United States with a diagnosis of COVID-19.Patients were divided temporally into different COVID-19 variant time periods depending on their time of admission to the hospital.Patients admitted between January 20, 2020 and July 5, 2021 were grouped into the wild type/alpha period, between July 6, 2021 and December 27, 2021 into the delta period, and between December 28, 2021 and February 14, 2022 into the omicron time period.The alpha variant became the dominant strain in the United States around March 2021, though it did not cause a marked spike in new cases.The wild type and alpha waves were combined for the purposes of this analysis.Date cutoffs were chosen a priori on the basis of the date at which the particular variant became the predominant strain in the United States. 3Patient demographic characteristics, medical comorbidities, vitals on hospital presentation, admission symptoms, medications before admission, laboratory reports, therapies received during hospitalization, procedures performed during hospitalization, and outcomes during hospitalization were compared between age groups within the variant time periods and across time periods within age strata.Continuous and categorical variables were compared across the variants using Kruskal Wallis and c 2 tests, respectively.
Using adjusted logistic regression, we evaluated the association of COVID-19 variant time period with in-hospital patient outcomes.Models were run separately for those aged 18-40 years (young) and for those aged more than 40 years (older).Further models were run evaluating the impact of age category (older vs young) on in-hospital outcomes.Outcomes included severe COVID-19, major adverse cardiovascular events (MACE), thromboembolic disease (deep vein thrombosis or pulmonary embolism), and in-hospital mortality.Severe COVID-19 was defined as patients experiencing mechanical ventilation, cardiac arrest, or death while hospitalized.MACE was defined as a composite of myocardial infarction, new-onset heart failure, stroke, or death while hospitalized.Last, multivariate cubic spline models were created to continuously model the impact of age on predicted probability of severe COVID-19, MACE, and inhospital mortality across all 3 COVID-19 variant time periods.Splines were constructed using 3 knots placed at evenly spaced percentiles.Logistic regression and spline models were adjusted for age (where appropriate), sex, body mass index, race or ethnic group, payment source, and medical comorbidities (atrial fibrillation or flutter, cancer, cerebrovascular disease, chronic kidney disease, congenital heart disease, coronary artery disease,   diabetes mellitus, dyslipidemia, heart failure, hypertension, immune disorders, peripheral artery disease, pulmonary embolism, pulmonary disease, and smoking).All statistical analyses were conducted using SAS on the AHA's precision medicine platform. 11A 2-sided P<.05 was set as a threshold for statistical significance.

RESULTS
The overall cohort consisted of 45,421 patients hospitalized with a confirmed diagnosis of COVID-19 between January 20, 2020 and February 14, 2022.Of these, 41,426 were admitted during the wild type/alpha variant time period, 3349 during the delta period, and 646 during the omicron period.The median age (95% CI) of the cohort was 63 years (50-75), and 46.8% of the group was female.The general demographic characteristics and medical comorbidities stratified by age group (young: 18-40 years and older: more than 40 years) and variant time period are shown in Table 1.Of the overall hospitalized cohort, 21.4% of patients were non-Hispanic Black or African American, and 19.4% of the group was Hispanic.Hospitalized patients were more likely to be non-Hispanic Black or Hispanic, and less likely to be non-Hispanic White during the wild type/alpha period compared with the delta and omicron periods in both age groups (Table 1).
When comparing admission characteristics, young and older patients were less likely to present with cough, fatigue, fevers or chills, headache, loss of taste or smell, nausea, vomiting, or diarrhea during omicron when compared with the other variant time periods.Patients in both age strata presenting during the delta period were more likely to present with shortness of breath, hypoxia, and with interstitial infiltrates on chest x-ray or computerized tomography (CT) when compared with the other periods.Older patients (more than 40 years) presented with increased rates of confusion or altered mental status, cough, fatigue, hypoxia, and interstitial infiltrates on chest x-ray or CT when compared with younger patients (18-40 years) across all variant time periods (Table 2).
When evaluating therapies received during hospitalization, patients in both age strata presenting during the wild type/alpha period were more likely to be treated with convalescent serum, hydroxychloroquine, and azithromycin, whereas patients presenting during the delta period were more likely to be treated with mechanical ventilation, inotropes or vasopressors, corticosteroids, remdesivir, and tocilizumab when compared with the other variant time periods (Table 3).When comparing age groups, older patients were more likely to receive corticosteroids, remdesivir, tocilizumab, mechanical ventilation, and inotropes or vasopressors when compared with younger patients across all 3 periods.In univariate analysis, older patients aged more than 40 years presenting during delta were found to experience more acute myocardial infarction, deep vein thrombosis or pulmonary embolism, in-hospital shock, and inhospital mortality when compared with the other time periods.Younger patients (18-40 years) were more likely to experience deep vein thrombosis or pulmonary embolism and in-hospital mortality during the delta period compared with the other waves.Rates of myocarditis and new-onset heart failure were low across all 3 variants.(Table 3).Rates of missingness are shown in the Supplemental Table, available online at http://www.mcpiqojournal.org.
In adjusted logistic regression models evaluating the association of COVID-19 variant time period on in-hospital outcomes among patients 18-40 years, patients presenting during the delta period had increased odds of severe COVID-19 (odds ratio [OR], 1.64; 95% CI, 1.29-2.08),MACE (OR, 1.76; 95% CI, 1.25-2.49),and in-hospital mortality (OR, 2.24; 95% CI, 1.51-3.32),and a decreased odds of discharge to home (OR, 0.69; 95% CI, 0.54-0.89)when compared with patients presenting during the wild type/alpha period.Young patients aged 18 to 40 years presenting during the omicron period were not found to have different odds of severe COVID, MACE, in-hospital mortality, or thromboembolic disease when compared with those presenting during the wild type/alpha period (Table 4).Among older patients (aged more than 40 years), patients presenting during the delta period were found to have increased odds of severe COVID-      b Models adjusted for sex, body mass index, race, payment source, and medical comorbidities (atrial fibrillation or flutter, cancer, cerebrovascular disease, chronic kidney disease, congenital heart disease, coronary artery disease, diabetes mellitus, dyslipidemia, heart failure, hypertension, immune disorders, peripheral artery disease, pulmonary embolism, pulmonary disease, and smoking) c Regression models compare outcomes of adults (>40 years) to young adults ( 40 years) 1.53-2.11),in-hospital mortality (OR, 1.44; 95% CI, 1.29-1.62),and discharge to home (OR, 1.15; 95% CI, 1.05-1.27)when compared with patients presenting during the wild type/alpha period.Older patients aged more than 40 years presenting during the omicron period had decreased odds of severe COVID-19 (OR, 0.66; 95% CI, 0.51-0.87)and in-hospital mortality (OR, 0.64; 95% CI, 0.45-0.91)but not MACE or thromboembolic disease when compared with patients presenting during the wild type/alpha period (Table 4).
In adjusted spline models continuously modeling the impact of age, increasing age was found to associate with increased predicted probability of severe COVID-19, MACE, and in-hospital mortality across the wild type/alpha, delta, and omicron time periods (Figures 1-3).

COVID-19 Evolution
The initial strain of COVID-19 (wildtype) was first discovered in Wubei Province, China in December 2019. 1 The virus itself was found to have 90 homotrimeric spike receptors on its membrane, with a mechanism of infectivity involving spike protein binding to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. 12As the wild type strain spread around the world, it began to acquire mutations, changing both its infectivity and severity patterns.Strains with mutations became known as variants, with alpha, delta, and omicron being the 3 main variants to date in the United States. 3The alpha variant was found to have over 12 main mutations in its spike protein, including 7 amino acid substitutions and 2 deletions. 12,13These mutations were shown to increase binding affinity, cell entry, infectivity, and transmissibility. 12The delta variant was found to have further spike protein mutations with resultant increased transmissibility, viral load, and ultimate ability to evade CD8 T cells. 6Last, the omicron variant was found to possess a marked degree of sequence variation, with at least 32 mutations in the spike protein alone. 5,12hese genetic mutations have created distinct patterns of transmissibility, infectivity, and severity, and indeed, previous studies have shown clinical differences between the different COVID-19 strains.[20][21][22][23][24] Clinical Presentation, Treatment Patterns, and Outcomes These previous findings are consistent with the results of our study.For example, patients of both age strata presenting during the delta period were more likely to present with hypoxia, dyspnea, and interstitial infiltrates when compared with the other strains, whereas those presenting during omicron were found to present with milder symptoms such as nasal congestion and were less likely to present with loss of smell or taste.With regards to treatments received during hospitalization, those admitted during the delta period were more likely to receive mechanical ventilation, corticosteroids, remdesivir, and tocilizumab when compared with the other variants.In adjusted models, both younger and older patients presenting during delta had increased odds of severe COVID-19, MACE, thromboembolic disease, and in-hospital mortality when compared with wild type/alpha.Among patients aged more than 40 years, those presenting during omicron were shown to have decreased odds of severe COVID-19 and inhospital mortality when compared to those presenting during wild type/alpha.The differences observed in clinical presentation, treatments received, and outcomes may in part be due to the virulence and location of predominant viral replication in the different variants.In laboratory studies, for example, omicron has been shown to replicate more in the upper airways and less in the lungs and may cause a milder form of disease. 25,26Decreased severity in symptomology and outcomes during omicron may also be attributed to greater rates of vaccination in those presenting during the omicron time period. 21One study from California reported that a greater proportion of patients admitted with COVID-19 during omicron were fully vaccinated (according to Centers for Disease Control definitions at the time) when compared to a period of delta predominance (39.6% vs 25.1%). 21There were also fewer unvaccinated patients hospitalized during omicron when compared with delta (56.4% vs 71.1%). 21Finally, previous studies have reported increasing percentages of hospitalized patients during omicron admitted for an alternate diagnosis who were found to incidentally have COVID-19, which may further explain the improved clinical severity and outcomes in this group. 27,28hen stratifying the cohort by age, we found increased odds of adverse outcomes in those presenting during the delta period compared with wild type/alpha among both young patients (age 18-40 years) and older patients (age more than 40 years).When evaluating the impact of age across each variant time period, we found increased odds of adverse outcomes among older patients compared with younger patients across all 3 variant time periods.Last, when continuously modeling age as a predictor of adverse outcomes, we show that increasing age associated with an increased predicted probability of severe COVID-19, MACE, and in-hospital mortality.0][31][32][33][34][35] Several reasons have been postulated for this association and include increased basal inflammation, hyperresponsiveness of immune cells, ineffective T cell priming, decreased T cell diversity, diminished antibody response or activity, and an unregulated innate immune system in those of older age. 36A higher prevalence of comorbidities, differential host receptor expression, and variations in coagulopathy have also been suggested to play a role. 29,32,37mitations Data included in this study are from voluntary participating institutions in the GWTG COVID-19 cardiovascular disease registry, and therefore may not be fully generalizable to the overall United States population.Fewer patients were enrolled during the delta and omicron periods from a smaller number of participating sites, which may further limit generalizability.We are only able to determine the time period during which patients were hospitalized with COVID-19, and so we are unable to determine the strain of the virus infecting the patient.The data gathered are observational, and therefore, causality cannot be established.The data and outcomes are only gathered from the patient's in-patient admission.Post discharge outcomes are not available.The vaccination rates of the cohort were not tracked.Although logistic regression and spline models were adjusted for possible confounders, residual confounding may still exist.

CONCLUSION
In one of the largest national COVID-19 analyses to date, we describe demographic, comorbidities, clinical characteristics, hospital treatment patterns, and outcomes for 45,421 patients admitted with COVID-19 in the United States between January 20, 2020 and February 14, 2022, stratified by patient age.Patients presenting during a period of delta predominance were found to have increased morbidity and mortality, whereas patients aged more than 40 years presenting during omicron reported decreased outcome severity when compared with those presenting during wild type/alpha.Increasing age adversely associated with outcomes across all 3 COVID-19 variant time periods.These data provide an important snapshot into the clinical characteristics and outcomes of hospitalized COVID-19 patients stratified by age during the first 2 years of the pandemic in the United States.

POTENTIAL COMPETING INTERESTS
Dr Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Eli Lilly, Janssen, Medtronic, Merck, and Novartis.Dr Parikh receives research support from the American Heart Association, Janssen, Infraredx, Abbott Vascular, and Bayer, and consulting fees from Abbott Vascular.Dr de Lemos reports consulting income from Eli Lilly, Novo Nordisc, and Astra Zeneca.Dr Yang reports research grants/funding from CSL Behring, Boehringer Ingelheim, Eli Lilly, and Bristol Meyers Squibb, and consulting fees from Pfizer.

TABLE 1 .
Characteristics of the Cohort Stratified by Age and Coronavirus Disease 2019 Variant Time Period a

TABLE 3 .
Hospitalization Characteristics and Outcomes of the Cohort by Age and Coronavirus Disease 2019 Variant Time Period a Continuous variables presented as median (25th-75th percentile).Continuous and categorical variables compared using Wilcoxon Rank-Sum test and c 2 tests, respectively.
b Comparison P value compares young or older groups across all 3 time periods.c b Comparison P value compares young or older groups across all 3 time periods.c

TABLE 4 .
Association of COVID-19 Variant Time Period with Outcomes Among Patients 18-40 Years and >40 Years Presenting with COVID-19 a,b Models adjusted for age, sex, body mass index, race, payment source, and medical comorbidities (atrial fibrillation or flutter, cancer, cerebrovascular disease, chronic kidney disease, congenital heart disease, coronary artery disease, diabetes mellitus, dyslipidemia, heart failure, hypertension, immune disorders, peripheral artery disease, pulmonary embolism, pulmonary disease, and smoking).c P value for overall COVID-19 wave effect; Wald c 2 test.
Splines reporting association of continuous age with predicted probability of death.